c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder

Contreras, Pablo S.; Tapia, Pablo J.; Gonzalez-Hodar, Lila; Peluso, Ivana; Soldati, Chiara; Napolitano, Gennaro; Matarese, Maria; Heras, Macarena Las; Valls, Cristian; Martinez, Alexis; Balboa, Elisa; Castro, Juan; Leal, Nancy; Platt, Frances M.; Sobota, Andrzej; et. al.

Abstract

The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEBdependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.

Más información

Título según WOS: ID WOS:000594408700002 Not found in local WOS DB
Título de la Revista: ISCIENCE
Volumen: 23
Número: 11
Editorial: Cell Press
Fecha de publicación: 2020
DOI:

10.1016/j.isci.2020.101691

Notas: ISI